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CytosolCytosol
HepatocyteHepatocyteApoB
DegradationDegradation
5' 3'
ApoB mRNA ApoB mRNA TranslationTranslation
ER
Mem
bran
eE
R M
embr
ane
InsulinIRS1/IRS2
IR
Insu
lin S
igna
ling
Path
way
Insu
lin S
igna
ling
Path
way
Plasma
Plasma
VLDLVLDL
Insulin Signaling & VLDL Overproduction Insulin Signaling & VLDL Overproduction in Insulin Resistancein Insulin Resistance
PI3-Kinase
VLDL AssemblyVLDL Assembly
PIP3/Phosphorylation CascadePIP3/Phosphorylation Cascade
Akt/PKBAkt/PKB
PTP-1BPTP-1B
3'
D
Insu
lin R
ecep
tor p
rote
in M
ass
(sca
nnin
g un
its/ m
g pr
otei
n x1
0-3)
Control Fructose-fed
Control Fructose-fed0
50
100
150
200
250
IRS
-1 P
rote
in M
ass
(sca
nnin
g un
its/m
g pr
otei
n x1
0-3)
Control Fructose-fed
Control Fructose-fed0
40
80
120
E F Control Fructose-fed
0
20
40
60
80
100
120
Control Fructose-fed
IRS
-2 M
ass
(per
cent
of c
ontro
l)
C
Pho
spho
ryla
ted
IRS
-2(r
elat
ive
to b
asal
leve
l of c
ontro
l)
020406080
100120140160180
_ + _+
Insulin
+ + + +Insulin _ _ _ _
Control Fructose-fed
ControlFructose-fed
Impaired Hepatic Tyrosine Phosphorylation of Insulin Receptor, IRS-1, and IRS-2
in Fructose-Fed HamstersA
Pho
spho
ryla
ted
Insu
lin R
ecep
tor M
ass
(sca
nnin
g un
its/m
g pr
otei
n x1
0-3)
Control Fructose-fed
0
100
200
300
400
500
600
_ + _+
Insulin
+ + + +Insulin _ _ _ _
*
B
_ + _+
Insulin
Pho
spho
ryla
ted
IRS
-1(s
cann
ing
units
/mg
prot
ein
x10-3
)
Control Fructose-fed
0
20
40
60
80
100
120
Control
Fructose-fed
+ + + +Insulin _ _ _ _
P= 0.04
P= 0.009
P= 0.02P= 0.03
P= 0.029
*
*
B
0
50
100
150
200
PTP
-1B
Mas
s(p
erce
nt o
f con
trol)
Control Fructose-fed
Control Fructose-fed
C
0
100
200
300
PTP
-1B
Act
ivity
(per
cent
of c
ontro
l)
Control Fructose-fed
A
0
20
40
60
80
100
120
PI 3
-Kin
ase
Act
ivity
(per
cent
of c
ontro
l)
Control Fructose-fed
* *****
D + + + +Insulin
020406080
100120140
Insu
lin-In
duce
d A
kt S
erin
ePh
osph
oryl
atio
n (%
of c
ontr
ol)
Control Fructose-fed
Insulin
_ + _ +
E
Insulin
Insu
lin-In
duce
d A
kt T
hreo
nine
Ph
osph
oryl
atio
n (%
of c
ontr
ol)
Control Fructose-fed
020
40
60
80
100120
_ + _ +
+ + + +
Insulin
F Control Fructose-fed
20406080
100120140160
Akt
Pro
tein
Mas
s (p
erce
nt o
f con
trol)
0Control Fructose-fed
****
***
*
Evidence for Reduced PI-3 Kinase Activity, Reduced Akt Phosphorylation, & Enhanced PTP-1B Mass & Activity
0
20
40
60
80
100
120
0 20 40 60 80
Vanadate (M)
Rec
over
ed C
ellu
lar A
poB
(rel
ativ
e to
unt
reat
ed)
B
0
20
40
60
80
100
120
0 20 40 60 80Vanadate (M)
Rec
over
ed L
abel
ed M
edia
Apo
B(r
elat
ive
to u
ntre
ated
)
C
Vanadate (M)
Rec
over
ed T
otal
Apo
B(r
elat
ive
to u
ntre
ated
)
0
20
40
60
80
100
120
0 20 40 60 80
D
Vanadate (M) 0 10 40 80
IR-pY
0
100
200
300
400
500
600
0 20 40 60 80Vanadate (M)In
sulin
Rec
epto
r Pho
spho
ryla
tion
(rel
ativ
e to
unt
reat
ed)
A
0 10 20 40 80Vanadate (M)
Cellular ApoB
Secreted ApoB
E
Inhibition of Cellular Phosphatase Activity with Vanadate Enhances Insulin Signaling and Reduces ApoB Secretion
IR-IR-ppYY
Cellular ApoBCellular ApoB
ApoB StabilityApoB Stability
ApoB SecretionApoB Secretion